Pharmaceutically useful compounds may be obtained from Rhus verniciflua which has been traditionally used in Korea, Japan and China in making a lacquer paint. For example, fisetin, fustin and other compounds have been found in the aqueous extract of the xylem of Rhus verniciflua (Hasegawa, M. and T. Shirato, J. Chem. Soc., 72, 223(1951)). Fisetin and fustin have pharmacological activity in: protecting blood vessel and capillary(Beretz, A. and Cazenave, J. P., "The Effect of Flavonoids on Blood Vessel Wall Interactions" in Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological and Structure-Activity Relationships, E. Middleton Jr. and J. B. Harborne, Eds., A. R. Liss, New York, pp 187-200 (1988)); suppressing the formation of peroxidized lipids(Kappus, H. et al., Pharmacol., 300, 179-187(1977); Baumann, J. et al., Prostaglandins, 20, 627-639(1980); and Yoshimoto, T. et al., Biochem. Biophys. Res. Commun., 116, 612-618 (1983)); and inhibiting allergy and dermatopathies(Loggia, R. D. et al., in Cody, V. et al.(eds), Plant Flavonoids in Biology and Medicine, A. R. Liss, New York, 481-484(1986)).
Besides fisetin and fustin, various other flavonoids such as agathisflavone, butein, corilagin, 3',4'-dihydroxy flavone, eicosanedioic acid, europetin, sulfuretin and quercetin have also been found in the plants of genus Rhus(Bukkingham, J. Dictionary of Natural Products, 7, 761(1994)). However, none of these compounds has been tested for their anti-cancer activity.
As well known, cancer is a disease caused by the impediment of cell differentiation and loss of control over cell growth. Recently, agents that induce cancerous cells to differentiate into normal cells, i.e., organ differentiation agents, have been studied to treat various forms of cancer(V. L. Stevens, et al., Cancer Res., 50, 222-226(1990)). In these studies, potential organ differentiation agents have been screened by employing an F9 teratocarcinoma cell model system. An F9 teratocarcinoma cell does not differentiate under a normal condition, but it transforms into a primitive developmental form when it reacts with retinoic acid, a synthetic organ differentiation agent. Further, this cell differentiates into a form similar to a coelomic wall when it reacts with a mixture of retinoic acid and dibutyryl cyclic AMP(Bt2cAMP) (Grober and Adamsom, Strickland and Sawey, 1980, 1986).
Such screening studies have shown that urusolic acid(UA), oleanolic acid(OA) and triterpene acid isolated from Eriobotrva laponica LINDL. are capable of differentiating F9 teratocarcinoma cells into normal cells. Further, urusolic acid and oleanolic acid have also been reported to have anti-cancer activity and to induce the differentiation of F9 teratocarcinoma cells by regulating the gene involved in the differentiation(Lee, H. Y. et al., J. Cancer Res. Clin. Oncol., 120, 513-518(1994)).
Angiogenesis, on the other hand, is a process of forming new blood vessels, which occurs in the embryogenesis and at the recovery region of a wound and corpus luteum. It has been reported that angiogenesis is indispensable for cancer cells to grow and propagate to various parts of the body by metastasis(Folkman, J. and Klagsburn, M., Science, 235, 442-447 (1987); Liotta, L. A., et al., Cancer Res., 34, 997-1004 (1974)). Accordingly, an agent that inhibits angiogenesis may be useful in blocking the metastasis of cancer cells after a surgical operation.
Retinoic acid and vitamin D3, which induce the differentiation of cancer cells to normal cells, inhibit angiogenesis as well(Okinawa, T. et al., J. Antibiot., 44, 1033-1035(1991)). However, there exist many problems in the clinical use of these angiogenesis inhibitors, due to their limited effect and high toxicity(Meeks, R. G. et al., Arch. Biochem. Biophys., 207, 141-147(1981)). Accordingly, various efforts have been made to identify and isolate non-toxic natural angiogenesis inhibitors from plants. In this vein, urusolic acid and oleanolic acid isolated from Eriobotrva japonica LINDL. have been reported to have some inhibitory activity on angiogenesis(Sohn, K. H. and H. Y. Lee, Cancer Letters, 94, 213-128(1995)).
However, there has continued to exist a need to develop a non-toxic anti-cancer agent which has an improved therapeutic efficacy.